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JAMM: A Metalloprotease-Like Zinc Site in the Proteasome and Signalosome

Ambroggio, Xavier I. and Rees, Douglas C. and Deshaies, Raymond J. (2004) JAMM: A Metalloprotease-Like Zinc Site in the Proteasome and Signalosome. PLoS Biology, 2 (1). pp. 113-119. ISSN 1544-9173. PMCID PMC300881.

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The JAMM (JAB1/MPN/Mov34 metalloenzyme) motif in Rpn11 and Csn5 underlies isopeptidase activities intrinsic to the proteasome and signalosome, respectively. We show here that the archaebacterial protein AfJAMM possesses the key features of a zinc metalloprotease, yet with a distinct fold. The histidine and aspartic acid of the conserved EXnHS/THX7SXXD motif coordinate a zinc, whereas the glutamic acid hydrogen-bonds an aqua ligand. By analogy to the active site of thermolysin, we predict that the glutamic acid serves as an acid-base catalyst and the second serine stabilizes a tetrahedral intermediate. Mutagenesis of Csn5 confirms these residues are required for Nedd8 isopeptidase activity. The active site-like architecture specified by the JAMM motif motivates structure-based approaches to the study of JAMM domain proteins and the development of therapeutic proteasome and signalosome inhibitors.

Item Type:Article
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URLURL TypeDescription CentralArticle
Rees, Douglas C.0000-0003-4073-1185
Deshaies, Raymond J.0000-0002-3671-9354
Additional Information:Received August 29, 2003; Accepted October 9, 2003; Published November 24,2003. DOI:10.1371/journal.pbio.0020002. Copyright: 2003 Ambroggio et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Academic Editor: Hidde L. Ploegh, Harvard Medical School *To whom correspondence should be addressed. E-mail: deshaies AT This work was supported by the National Science Foundation Graduate Research Fellowship and the Gordon Moore Foundation (to XIA), as well as the Howard Hughes Medical Institute (to DCR and RJD). We would like to thank the staff at the Stanford Synchrotron Radiation Laboratory, a national user facility operated by Stanford University on behalf of the United States Department of Energy, Office of Basic Energy Sciences, and the Advanced Light Source, which is supported by the Director of the Office of Science, Office of Basic Energy Sciences, Materials Sciences Division of the United States Department of Energy under contract number DE-AC03-76SF00098 at Lawrence Berkeley National Laboratory. Special thanks go to R. Verma and G. Cope for assistance with the associated biochemistry, T. Yeates and O. Einsle for insights concerning the treatment of the pseudocentered crystals, K. Locher and P. Strop for helpful discussions, and J. Ambroggio for back massages and constant support. Conflicts of interest. The authors have declared that no conflicts of interest exist. Author contributions. XIA, DCR, and RJD conceived and designed the experiments. XIA performed the experiments. XIA, DCR, and RJD analyzed the data. XIA, DCR, and RJD contributed reagents/materials/analysis tools. XIA wrote the paper.
Funding AgencyGrant Number
NSF Graduate Research FellowshipUNSPECIFIED
Gordon and Betty Moore FoundationUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Department of Energy (DOE)DE-AC03-76SF00098
Subject Keywords:AfJAMM, A. fulgidus JAMM protein; AMSH, associated molecule with SH3 domain of STAM; CDA, cytidine deaminase; CSN, COP9 signalosome; Cul1, Cullin 1; DUB, deubiquitinating enzyme; JAMM, JAB1/MPN/Mov34 metalloenzyme; MAD, multiwavelength anomalous diffraction; MPN, Mpr1p Pad1p N-terminal domain; Nedd8, neural precursor cell expressed, developmentally downregulated 8; RMS, root-mean squared; Rpn11, regulatory particle number 11; SCF, Skp1/ Cdc53/Cullin/F-box receptor; ScNP, S. caespitosus zinc endoprotease; Ub, ubiquitin; Ubls, ubiquitin-like proteins; UBP, ubiquitin-specific protease; UCH, ubiquitin C-terminal hydrolase
Issue or Number:1
PubMed Central ID:PMC300881
Record Number:CaltechAUTHORS:AMBpb04
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:261
Deposited By: Archive Administrator
Deposited On:13 May 2005
Last Modified:02 Oct 2019 22:31

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